I’ve been writing a lot about dichloroacetate (DCA) lately, perhaps even to the point of becoming repetitive and risking boring my readers. Fortunately, this post is not primarily about DCA. Unfortunately, it’s about a question that is related to the recent hype over DCA in that it pits the desperation of dying cancer patients who want to try out the latest drugs, even if they haven’t been demonstrated to be safe or efficacious, versus the what remaining ability the FDA has to regulate drug safety and, some might argue, the scientific method itself. It’s about a ruling that set a very disturbing precedent that patients have a “Constitutional right” to the being able to obtain potentially life-saving drugs even in the early stages of development. Because the article comes from a newspaper whose web articles expire rather rapidly, I’ll be fairly generous about quoting:

She was unable to get into a clinical trial for ImClone’s now widely available Erbitux because it was for colon cancer patients only, and she failed to meet the clinical trial inclusion criteria for Iressa, an AstraZeneca cancer drug that later proved largely unsuccessful.

At the end of May 2001, Burroughs was finally accepted into a clinical trial for OSI Pharmaceutical’s subsequently approved cancer drug Tarceva, but she was too ill to travel from Virginia to the Texas testing site. She died two weeks later at age 21.

“It was a horrible, horrible nightmare. When your child is terminally ill, you want to do everything you can,” said her father, Frank Burroughs of Fredericksburg, Va. “People just want a chance to live when they are facing death.”

Burroughs soon formed the Abigail Alliance, an organization dedicated to helping cancer patients and others with life-threatening illnesses break down barriers imposed by the Food and Drug Administration and the pharmaceutical industry to obtaining potentially helpful experimental drugs outside the clinical trial setting.

His relentless campaign has resulted in a court ruling that threatens to shake the foundations of the FDA’s regulatory authority covering pharmaceuticals and lead to greatly expanded use of unapproved medications that haven’t been fully tested for safety or effectiveness.

The legal battle, ironically, comes as medical experts, members of Congress and consumer groups have been criticizing the FDA for letting problem drugs on the market and then not properly monitoring their safety.

In a case to be reargued March 1 before 10 members of the U.S. Court of Appeals for the District of Columbia, a three-judge panel last May ruled dying patients have a constitutional right to purchase unapproved experimental drugs that have completed the initial Phase I human clinical testing if their doctors say there are no other viable options.

Just as terminally ill patients have a right to die by refusing medical treatment, the court said in a 2-1 decision, individuals have a fundamental right to “self preservation” that includes being able to obtain potentially life-saving drugs in early stages of clinical development.

The FDA is vigorously contesting what it calls “a profoundly troubling ruling,” arguing the appeals court has placed its ability to ensure patient safety in “a constitutional straight jacket.”

By weakening its discretionary authority, loosening the standards and allowing large numbers of patients to take drugs after small Phase I trials, the FDA said, the court’s ruling could create unacceptable risks, hasten patient deaths and undermine the science-based clinical trial system.

Oddly enough, I hadn’t been aware of the Abigail Alliance. I can fully sympathize with the parents who had to watch their child die of a horrible disease. I can even understand that they might believe that Erbitiux or Iressa may have saved her, even though in retrospect we know that it’s unlikely that either drug would have. Unfortunately, the ruling that the Abigail Alliance is pushing for could potentially have a very grave effect on the ability of the FDA to regulate drug safety, and it’s no surprise that the FDA is appealing it vigorously. Worse, it could jeopardize the development of the very drugs that it purports to want to make more widely available.

Before you can understand why, you need to understand what a Phase I clinical trial is. Basically, Phase I clinical trials represent the very first time a promising new substance is ever given to humans. The intent is not really therapeutic. Rather, it is to gather toxicity data and to determine the optimal dose. Basically, what is done is something called a dose escalation, where increasing doses are tried until toxicity is observed. The usual patients enrolled in these trials when done for cancer drugs have advanced disease that is incurable with present modalities. One reason for this is that in many cases it would be unethical to try such drugs out in patients who could expect to have a chance at long-term survival using conventional treatments, and that healthy volunteers would be unlikely to be willing to undergo the risk of toxicity from these very powerful drugs. Another reason is that sometimes we can see anti-tumor activity even in a phase I trial. However, it is not expected that antitumor activity will be observed, and not observing activity would not preclude moving on to a larger, randomized Phase II trial, in which the drug is tested against specific tumors.

What the Abigail Alliance is arguing for is to be allowed access to drugs that have only passed Phase I. At this point, there is usually no evidence of efficacy yet, and only the nastiest of the drug’s side effects are known. As the article points out, nine out of ten drugs tested in Phase I trials end up being abandoned, either because of excessive toxicity or because they don’t work. One example is amonifide for advanced breast cancer, which was discontinued after safety concerns emerged in a phase 2 trial. The trial demonstrated that amonifide resulted in serious hematologic toxicity (severe and life-threatening leukopenia and thrombocytopenia) and systemic allergic reactions. Expanding access to drugs that have passed Phase I would be likely to harm far more patients than it would potentially help, something the judges seem not to have considered. Indeed, they went so far as to infer that drugs showing success in phase 1 trials would “probably have a medical benefit with sufficiently minimal risk,” an inference that is breathtaking in its arrogance and ignorance.

However, there is a deep strain in American society between individual autonomy and the needs of society, and where that struggle is resolved often shifts over time. Peter Jacobsen describes the conflict and the dilemma:

Peter Jacobson of the University of Michigan Center for Law, Ethics and Health said the Abigail Alliance case presents a classic conflict between individual rights and the broader needs of society.

“Do I want to be the doctor telling a dying patient he has nothing to offer? No. Do I want to be the regulator saying you are not eligible for compassionate use of an experimental drug? No,” said Jacobson “But if I am a regulator and I say you can have anything you want, how do I protect patient safety?”

Jacobson said he believes “the future of pharmaceutical regulation is at stake,” with affirmation of the court decision opening the floodgates to “snake oil” remedies, offering “false hopes” and unleashing dangerous, unproved medications on the public. He said the integrity of the scientific and regulatory processes must take precedence over individual demands, no matter how heartbreaking.

This is particularly true because violating the integrity of these processes to make essentially untested drugs more widely available, is far more likely to harm the individual patient than to help him. If there’s anything worse than dying of a terminal illness. It’s dying of a terminal illness and suffering unnecessary complications or pain for no benefit and having to pay for the medications causing the complications yourself. In addition, we would risk seriously undermining the scientific basis for evidence-based medicine by undermining the whole system of clinical trials that studies efficacy and safety. After all, if early stage experimental drugs were available outside of clinical trials and were taken for a wide variety of cancers, it the signal-to-noise ratio would become very low, and it would become very difficult to tell which drugs were working and for which cancers (and which were not), particularly since it would be reasonable to expect that such a policy would result in enrollments in clinical trials plummeting. And what would be the potential payoff for this shredding of patient protections? Little at best, if even any at all. In reality, the likelihood of saving the lives of even a few cancer patients by giving them access to early experimental drugs is quite low and hard to justify on a moral and practical basis, given the likelihood of potential harm or premature death to so many other patients through the damage or destruction of a system that has been built up at such cost over several decades.

The entire ruling also seems to rest on a misperception that there are “miracle drugs” out there that we will have to wait years for because the FDA is too slow to approve them. However, if there really were such a “miracle drug” that was amazingly effective compared to anything we have now, a large randomized phase III trial would not be necessary to detect its efficacy. Indeed, its efficacy would almost certainly show up in even a small phase I trial. There’d be examples of amazing tumor shrinkage or even outright cures. In reality, we don’t see these things in Phase I trials, because there are no miracle drugs, at least not yet. Because the effects of most new drugs against various tumors tends to be less than miraculous, we need Phase III trials to determine safety and efficacy. It would be truly fantastic if we didn’t, but we do. If the ruling stands, the FDA really will be hamstrung. This seems a truly odd thing to want to do, given the high profile failures of the FDA to assure the safety and efficacy of various drugs. Indeed, in September, the Institute of Medicine released a report that was highly critical of the FDA and a rule passed by Congress in 1992 that allows pharmaceutical companies to pay the agency substantial fees to expedite reviews of their drugs. The report also criticized Congress for failing to fund FDA adequately for post-approval drug monitoring, citing Vioxx, the arthritis drug that was withdrawn in 2004 after it was found to double the risk of heart attack. For those out there who think that the FDA is a lapdog of big pharma, if this ruling stands it won’t have to be a lapdog to be totally ineffective. Worse, in a spectacularly misguided action, Senator Sam Brownback (R-Kansas) is pushing a piece of legislation that would in essence grant access to experimental therapies to patients with “serious or lifethreatening” illnesses.

Indeed, if it is ruled a “Constitutional right” to be able to use any experimental drug that has passed Phase I testing or if Senator Brownback’s bill passes, it could open the door to all sorts of dubious therapies being marketed:

Brownback’s bill stipulates that drug companies cannot be held liable for a patient’s adverse reactions to an experimental medication. But this may not be enough to reassure pharmaceutical companies, and it could inadvertently encourage retailers of alternative therapies that have little or no basis in science. “The bill opens the space for products that are sold by charlatans,” said David Parkinson, an oncologist who worked at the National Cancer Institute for many years and is now a senior vice-president at the biotech company Biogen Idec. One of Parkinson’s tasks at the N.C.I. was to evaluate herbal remedies and animal extracts, such as shark cartilage, that are sold in health-food stores and on the Internet, accompanied by testimonials from patients about their anti-cancer benefits. Some of these products could pass Phase I trials, Parkinson said, and, under Brownback’s bill, the F.D.A. would be compelled to approve them.

Such a bill or ruling could also put physicians in an ethically troublesome position, as Peter Jacobsen also points out:

In reality, that approach might prove problematic for physicians, leaving them caught between patient demands for ineffective or dangerous pharmaceuticals and physicians’ ethical obligation to do no harm. Perhaps even more troublesome, it would encourage the antithesis of evidence-based medicine.

The essence of the alliance’s clinical argument is that terminally ill patients should have the choice of using experimental drugs in consultation with physicians. “All [the plaintiffs] ask is that the government get out of their way, so that they can use their own private resources to fight for their own lives at the inherently uncertain frontiers of modern science.”20(p31) Consistent with current market theory, the panel’s opinion shifted the risks to the patient but also to the physician.

Physicians already face considerable pressure from patients who demand medications that are heavily marketed through direct-to-consumer advertising. As contentious as such advertising has been, allowing access to unapproved pharmaceuticals places physicians in the uncomfortable position of prescribing drugs with unknown risk profiles that may be more harmful than beneficial, explaining to patients why simply calling something lifesaving does not make it so, or being candid that medicine has nothing more to offer. While this is precisely the risk-benefit discussion that physicians should be having with patients, there is a substantial added burden when discussing drugs that have not completed appropriate clinical trials, especially when no data or published reports exist to support the physician’s professional opinion of safety and efficacy. As the government argued to the panel, terminally ill patients are particularly vulnerable to promises that unproven treatments will be effective.

Don’t even get me started on the liability issues involved. It’s impossible to give truly informed consent regarding a drug that hasn’t made it through at least Phase II testing. Given the litigious nature of the U.S., it’s highly unlikely that a blanket immunization from liability to physicians prescribing such drugs or drug companies making them would pass muster. And the flip side of the coin, of course, is that it is possible to imagine physicians being held liable for not pursuing experimental therapies.

Worse, none of this would prevent drug companies from advertising or publicizing their new drugs by word of mouth or viral marketing campaigns. Also, the Internet is a powerful tool that would almost instantly spread hype about new drugs far and wide. In essence, this policy would open the door not just to quacks and alties selling dubious remedies to cancer patients but to big pharma profiting from experimental drugs before they are even shown to be safe and effective. I point to the DCA kerfluffle again as further evidence for how hype and promises of a cancer cure can prey on desperate people. Here was a report of a drug that had shown promise in cell culture and in rat tumor models but had yet to be tested in humans against cancer, and the blogosphere goes wild. We have, as I pointed out, patients looking to buy the stuff, even though the sources cited as selling it aren’t selling pharmaceutical grade DCA, and I’ve even come across medical ignoramuses like David Springer (a.k.a. “DaveScot”) encouraging this behavior with a “wink-wink, nudge-nudge” disclaimer that he is “not encouraging anyone to self-medicate” and intends his message “solely to get the attention of established clinicians with experience in orphan drug testing.”

Yeah, right. Sure he isn’t and sure he does.

It could be argued that the FDA was too restrictive in the past in approving new drugs, but it can now be argued that it is in danger of moving too far in the other direction. For example, the FDA has moved, starting at the behest of AIDS activists and continuing under the urging of activists for various other diseases, to increase compassionate and expanded use programs and to developed an “accelerated approval” program for drug approval. The problem is that this “accelerated” program, originally intended to be used only for drugs designed to treat life-threatening diseases for which time is of the essence (such as AIDS) has now morphed to the point where it can be used for nearly any drug approval. (Indeed, Vioxx, hardly a drug designed to treat such diseases, was approved under the “accelerated approval” program, and look what happened there. There have been other problems with drugs approved under this program.)

The bottom line is that there will always be a conflict between wanting to do something now for suffering patients, damn the consequences, and following the scientific method to demonstrate efficacy and safety. Our nation has been at both extremes. Indeed, until 1906, pharmaceutical companies could make essentially any claims and sell essentially anything to the public as a drug without regulation. We all know how well that worked out. Early in the history of the FDA, as Dr Jerome Groopman points out, companies often tested new drugs by sending them to doctors to offer to their patients, asked for little information regarding side effects and complications, and had no standard criteria for efficacy. Do we really want to go back to those days? That’s where we seem to be heading. From my perspective, the National Organization for Rare Disorders seems to have a better and less dangerous summed it up well:

I understand the emotion that drives the Abigail Alliance, but this isn’t about emotion, it’s about saving as many lives as possible and not about getting as many drugs out as possible. It’s about doing the right research and making sure we have patient protections in place and making drugs available that are truly helpful.

As physicians, we must remember our charge, “First, do no harm.” Expanding the access to unproven drugs after only the minimal testing of a Phase I trial, many of which will turn out not to be efficacious and for which patients may have to pay out of pocket would be failing in that charge.

Comments

I don’t see what the problem would be as long as the patients consent to treatment with full knowledge of the fact that the safety and efficacy of the drug is not known. I don’t see how this would impact marketing – the drug companies couldn’t claim that the drug was safe or effective for treating the disease at that point, in ads or otherwise, and the problem with quack treatments is that those who are selling them are misleading the customers about the existence of scientific evidence for the treatment’s efficacy.

Speaking from the patient perspective, I want my doctor to give me accurate information about the risks and benefits of the treatments that are available, but the course of treatment should ultimately be my choice. It would be remiss for a doctor not to tell me that about 90% of the drugs in phase I trials do not turn out to be safe and effective, but the decision of whether to take that risk with an experimental drug should ultimately be mine.

Wouldn’t this basically put these experimental drugs into the same category as nutritional supplements? In other words, both these groups have not been shown to be safe or effective, yet people take supplements like they were candy, to the tune of billions of dollars a year.

If anything, this would create a disincentive to test drugs, because it could close off a profitable product. If you’re a drug company selling an unproven drug to desperate cancer patients across the country, why would you want to do research that would show it was ineffective?

1) By allowing for the selling of drugs without having them undergo full clinical trials (especially as per Brownback’s bill), pharmaceutical companies will see far lower market forces to design safe and effective drugs. The fact is that if you’re increasing the number of drugs you can sell by 1000% (presuming that previously 9 out of 10 failed after Phase I), this creates a better business model than the constant search for a patentable blockbuster drug that Big Pharma currently relies on. That is, market forces would now encourage the widespread production of sham medicine rather than real medications.

2) Who would be liable for the massive deaths resulting from the aforementioned problems? If we offer immunity to liability, people will be dying on poorly produced medicine and there will be no one to turn to – don’t imagine that this won’t cause massive legal rows all throughout the healthcare community. If someone -is- held liable, no one would be foolish enough to sell the products in question – resulting in more suits to allow consumer’s access to that which they’re legally entitled to. But how can the Pharma companies truly be liable, when the drugs are being sold before anything is truly known about them – can you blame them for selling dangerous drugs if people are buying them before the tests are fully completed that would ALERT the companies to the fact those drugs are dangerous?

3) Laws for the regulation of drugs are supposed to balance the possible benefits of allowing people access versus possible risks. Where the risks are so large, and the benefits are so small, this clearly falls into the category of heavy regulation. This is the same as any other dangerous recreational drug. That’s right, recreational – it does not constitute a ‘therapeutic’ drug until it has actually demonstrated therapeutic value, which these laws would preclude by selling the drugs before such testing occurs. Drugs without any established therapeutic value are thus at best recreational, and do not constitute a “course of treatment” – and as such, you have no right to select it “just because.”

4) As a matter of ethics, patients’ wishes are only listened to when the decision made is an INFORMED DECISION. This is, frankly, why insane and pediatric patients do not make their own decisions – when one can not properly receive, process, and act on the information offered one can not engage in the act of autonomously dictating treatment. There is some debate in the medical communities whether any treatment can be given in an “informed” manner – when fully trained doctors disagree on treatments, can a layman make an “informed” decision? In this particular instance, you are suggesting patients be given the opportunities to make EXPLICITLY uninformed decisions – with absolutely no knowledge about the drugs’ possible effects (therapeutic or adverse), the decision can not be anything but uninformed. This by itself constitutes an unethical situation for physicians, and overrides any desires of the patient (patients often want to do a number of stupid things; as individuals they are free to engage in these behaviors but it is not the healthcare community’s job to indulge them).

Frankly, where “alternative” medicines so frequently prey on the desperation of seriously ill people, offering an alternative from reputable and legitimate sources (though the alternative in question is in no way garaunteed to be safer for it) will do nothing for patient health – it will merely spread the same way homeopathic crap does, to the detriment of all of the seriously ill and overly-emotional people it aims to help.

No, it wouldn’t quite make such drugs the equivalent of nutritional supplements for the simple reason that, to get to the level of a Phase I trial, a new drug has to have undergone extensive testing in cell culture and animal models. And then a Phase I trial documents the worst of the toxicities (called dose-limiting toxicities). That’s a lot more than can be said about many nutritional supplements. However, it is not enough, as efficacy is usually not demonstrated in Phase I studies. Occasionally evidence of efficacy pops up in Phase I trials, but more often it doesn’t.

James:

Good points, all. I think the best one is the ethical consideration. I as a physician will not prescribe, for example, “alternative medicine” for which there is not convincing evidence of efficacy. If a patient wants to get it on his or her own, there’s nothing I can do about it other than tell that patient there’s no good evidence of efficacy, but I am not obligated to help them get it. The same would be true of using an experimental drug outside the confines of a well-designed clinical trial that minimizes the potential for harm and closely monitors the patients.

One point where I’d quibble is that it wouldn’t necessarily mean the widespread marketing of “sham” medications. They’d probably be, for the most part, better than altie nostrums for the reasons above: At least they will have demonstrated some sort of activity in cell culture and animal models, and at least there will be some data on dose-limiting toxcities in humans. I’d look at it more this way: If all a drug company has to do to get a drug sold to terminally ill patients is to get it through a Phase I trial, then the bar is lowered. More drugs would be pushed into the Phase I pipeline, most likely decreasing the percentage of drugs that actually actually make it to full FDA approval. In the meantime, the drug companies could make considerable money off of the drugs tht passed Phase I but never made it any further. They could also make money off of drugs that ultimately do make it all the way through to FDA while they’re still being tested–in essence, subsidizing the cost of deveopment by selling such drugs to desperate people before there’s sound evidence of efficacy and safety.

The effect of the Brownback Bill and/or failure to overturn this ruling would likely be catastrophic for drug development.

Matt:

I’ve heard your argument before, and it is a seductive argument. However, even the most libertarian society has to balance the good of the individual versus the good of society. There is no inherent “right” to take experimental drugs, particularly if granting that “right” would endanger so many others while being highly unlikely to benefit any but a very few patients, if even that.

I believe there should not be a constitutional right to take experimental drugs per se, but it SHOULD be a right of every person with a life-threatening illness to participate in the testing process. That’s a subtle, but important distinction.

I agree that allowing unfettered access to virtually untested drugs would be catastrophic. However, given the real and desperate need of many people with life-threatening illnesses for new treatment options, the solution here seems obvious: expand clinical trials. If someone really wants/needs to try a new drug, let them – but monitor it for safety and efficacy. Larger trials would actually help increase the safety of drugs and help determine which tumors etc. they are most effective on. Aside from cost, there is no disadvantage to testing a drug on a person whom it COULD help, as that is data you wouldn’t have had otherwise.

I worked with cancer patients for the past year (in a support/psychological, non-medical capacity) and have seen how much hope they have thanks to clinical trials and how hard and desperately they try to get accepted into them. It shouldn’t have to be that hard. It shouldn’t depend on who you know, whether you can afford travel costs, whether you’re computer and phone-savvy enough to find a trial, or whether you come from an educated background and know how to work the system. I’m not saying all people in clinical trials have those advantages, but many do, and that isn’t fair.

Ayesha, when everybody had a right to participate in clinical trials, other problems would arise, e.g. who would pay for that? OK, this sounds cynical, but AFAIK you need to meet certain criteria to participate in order to make the results of the trial comparable (age, gender,…), to generate good data.
Pharma companies and their investors (meaning we all through pension funds and insurances, never forget that) only invest in these trials because they need them to get the drug approved and to get a ROI (and because it would be unethical not to do them). If you had a lot of people in the trial that you could exclude from the beginning, then somebody would have to cover the costs for them and I don´t think that the patient could afford that and why should the company? That leaves society and that for an unproven treatment.
If that legislation passes then I would set up a company for quick&dirty PhaseI trials of every alternative treatment that is out there and get filthy rich.
No more testimonials, my stuff would have passed clinical trials!

As an afterthought: Would this really be a disincentive for further trials? What about reimbursement, wouldn´t only FDA-approved drugs be covered and be lucrative?

Yes, only FDA-approved drugs would be covered by insurance and government medical plans. What I meant was that the Brownback bill could result in an incentive to rush more drugs into Phase I trials, thus decreasing the signal-to-noise ratio of good drugs to failed drugs, because they could expect to make at least some of their research and development investment back even on drugs whose testing and development are abandoned.

Two other aspects:

1. Drug companies usually only make small amounts of experimental drugs, usually only slightly more than enough for clinical trials. If demand were expanded through such a “Tier I” program, they’d probably be forced to ramp up production facilities before they even know that the drug will be FDA-approved.

2. Right now, under most “compassionate use” or “expanded use” programs, the patient doesn’t have to pay for the drugs; the drug companies in essence give away the drug. They can afford to do this now because relatively few people qualify for such programs. However, if such programs were expanded to the extreme of the Brownback bill, you can bet that drug companies would start charging patients for experimental drugs, and charging them a lot. And, of course, insurance wouldn’t pay. This would have the end result that these experimental drugs would be denied to the poor.

“…it SHOULD be a right of every person with a life-threatening illness to participate in the testing process.”

I think that it is very unwise to expand people’s “rights” to have someone else pay for their medical care.

A true “right” is something that you can exercise on your own, as long as you are allowed to do it. The right to free speech does not entail a “right” to get on your local radio or television station to disseminate your views. The right to practice the religion of your choice (which includes the right to practice no religion) does not entail an obligation for the community to build you a place of worship.

Giving people a “right” to participate in drug testing studies would collide rather directly with the drug companies’ “right” to carry out these FDA-mandated studies without being forced to include more people than necessary or people who do not meet the inclusion criteria.

Folks need to keep in mind the Law of Unintended Consequences: while the intention of the Brownback bill may be to give people access to new potential therapies, the unintended results will be:

[1] Drug companies will have a disincentive to proceed beyond Phase I trials – once a drug passes those trials (which are much less expensive than Phase II and Phase III), why would they want to kill off 90% of their current money-makers by completing Phase II trials? I would expect to see Phase II trials prolonged for years, if not decades, in order to keep profitable drugs “on the market” despite problems with efficacy or safety.

[2] As mentioned above, who pays for the people harmed by drugs that have only passed through Phase I?

[3] At first, insurance and government programs will not pay for these untested drugs, but expect to see mounting pressure (backed by innumerable testimonials and sob-stories) to have yet another law passed mandating that insurance (and Medicare/Medicaid) pay for them.

[4] I would also expect to see a push – since those with life-threatening illnesses have a new “right” – to force the pharmaceutical companies to accept all comers into their drug trials without compensation. Once this becomes a reality, drug testing will bog down under the weight (and cost) of the thousands of people lining up for free drugs.

The biggest danger from government is when some politician decides that “something needs to be done” and sets about to do it without understanding either the problem or the ramifications of the solution (which is most of the time).

Slowly but surely, Congress is dismantling the safety features of the FDA. First, they let anything that could be called a “supplement” get around the FDA. Now, they want to allow people to have essentially unfettered access to drugs that have only passed the first phase of human testing.

The current bill is supposedly for those with “life-threatening illnesses”, but the devil is in the details. Who will define what is a “life threatening” illness? Will it be limited to cancer, or will heart failure, diabetes, Lyme disease and autism eventually be classified as “life threatening” for the purposes of this law.

I think you all underestimate the ability of individuals to make rational choices, and undervalue personal freedom. I do not accept this claim that it is by nature an uninformed choice to take one of these Phase-I drugs. The patient would be told by the doctor that only 1 out of 10 of Phase-I drugs every show efficacy, and often only for a very particular set of health conditions that the patient probably does not have. What more do you want?

Many of you seem to fear large distortions in the incentives for drug companies, but I don’t see it. As you said, “If there’s anything worse than dying of a terminal illness. It’s dying of a terminal illness and suffering unnecessary complications or pain for no benefit and having to pay for the medications causing the complications yourself.” The patient knows that there is a >90% chance that this will be the case. This is a pretty strong incentive. If he also knows that he has a 99.9% chance of dying without trying the drug, and if he has the means to pay for the drug, who are we to decide it is time for him to stop hoping? Yes, some people will make irrational choices. We should not limit everyone because of those few. The drug companies will still have incentive to continue phase-II and phase-III trials because those drugs that demonstrate effectiveness will be widely used.

As for the argument that the experimental drugs would be denied to the poor, you have already made the argument that it is extremely unlikely that the drugs would be of any benefit to anyone. Many, many non-essential things are denied to the poor. Is there really an argument to be made that the poor should be provided with useless non-essential things.

You say it comes down to balancing between individual autonomy and the needs of society. I think you need to make a much stronger case that a few terminally ill people will impose a significant cost on society by spending their own money on something that affects only them.

People are allowed to gamble with their lives and comfort in many ways. Dying people should have more, not less, freedom to do so.

As for the argument that the experimental drugs would be denied to the poor, you have already made the argument that it is extremely unlikely that the drugs would be of any benefit to anyone. Many, many non-essential things are denied to the poor. Is there really an argument to be made that the poor should be provided with useless non-essential things.

That entirely depends on the type of drug. There are a lot of studies that provide people like me, with access to mental health drugs and the care that goes with them – some including weekly or bi-weekly sessions with a therapist. With a lot of these drugs, especialy ones dealing with anxiety disorders, it is already likely they will have at least some efficacy. That coupled with simply seeing a doctor, means that a lot of people who have been unable to recieve any care, can get something. Even if the study isn’t right for them, the doctor they see can often get them a refferal for care, through public providers.

I am on a waiting list to get into one of these studies. Barring that, I am at least six months out, from getting an evaluation for real help. Going into one of these studies, either means getting care through the study, and/or getting bumped up the waiting list for public care. Even if a drug that was being studied on me ultimately proved problamatic, it is a huge net gain for me and people like me.

Most drug studies that I have heard of – through friends and looking into them myself, offer a lot of benifits to those who partake – usually the poor or terminaly ill. They are often times, big pharma at its most benevolent. My old roomie gets a lot out of an HIV study he is part of. Aside from knowing that he is helping others who have HIV/AIDS, he also gets some of his meds free (he is on a lot of drugs), he gets a handfull of $10 gift cards for the local grocery/department store and preferential treatment from DHS (because the study covers all of his HIV drugs, at over $1300 a week and some of his other meds, saving the Ryan White fund and the state, a lot of money). They also give him a huge number of public trans tickets, whenever he has to go in.

Drug trials are just a great way for the un/under-insured, to get care for cronic health issues, that otherwise must be ignored. Often, this also means they get care for other health concerns, either as payment or because not getting the care would interfere with the study. Percentage wise, it is probably not a huge source of care, but for those who need it, it can be quite invaluable.

I work for a biotech company that specialises in developing cancer drugs so I read Orac’s blog with great interest. I had a couple of thoughts on this that perhaps are specific to an industry perspective.

First, the most a pharma company would receive for an unapproved drug given to a trial ineligible patient would be the manufacturing cost. The reimbursement price of a drug post-approval is far higher than the cost price – often many multiples of it. So there would still be a strong incentive for a company to continue the development process, even if they could provide ineligible patients with unapproved drugs.

Second, if companies were obliged to make supplies of investigational drugs available to patients ineligible for clinical studies, it could mean that the studies themselves were delayed or even not completed due to lack of product. As Orac mentioned above, most companies manufacture only enough to complete a study. And you usually want to complete an entire study with the same batch of material, for the sake of consistency, not manufacture more half way through. For a biotech company in particular, having to manufacture an indefinite amount of additional material to supply non-trial patients could compromise the ability to supply the patients in the study. In the worst case, there are biotech companies operating on a shoestring that could go bankrupt without completing a study. This sounds alarmist, but one well-known historical example is Amgen, which was unable to pay its employees in the time running up to approval of Epogen. SO one risk of forcing companies to provide unapproved drugs to trial-ineligible patients would be that potentially life-saving drugs would be lost.

In cancer especially this is a very pressing question. Although all patients have the right to enter a study, the majority, often including the most advanced and sick patients, will not be eligible. For example, patients with co-morbidities or poor performance status are often excluded. So their access to experimental medicines is limited, and for those patients there are named patient and compassionate use programmes run by major pharma companies to enable access to at least some experimental drugs. I would like to see access widened, but I find it difficult to think of a practical way that it could be achieved.

I find the Abigail lawsuit baffling for many reasons, primarily because FDA has no jurisdiction over the sponsor and cannot order the company to provide a drug for use.

Seems like the main obstacle to the reasonable use of investigational agents by “trial inelligible patients” is the drug sponsor, and not FDA. Thank you, Mel, for providing this term.

I think there are many times when the use of investigational therapies can be more reasonable than approved protocols. Otherwise, it would be unethical to do any study.

Treating physicians are often unaware of investigational options; they may sometimes be unmotivated or too busy to do the research. This appears to be one reason for low participation rates in clinical trials. There are many.

The informed patient seeking expanded access to an investigational treatment (agent or protocol) has many obstacles. First, the case must be made to his or her treating physician, or vice versa. Next, the physician must contact the sponsor to determine if the company will or can make it available. (Note: There’s no incentive for the sponsor to do so, and many potential liabilities in an off-study use of a new drug nicely described above.) Next, the physician or sponsor must complete the expanded access paperwork for FDA approval. In my view, and from personal experence, this can be the easiest part. Finally, the physician must get an IRB approval of the protocol and the informed consent document, etc.

FDA is working on a revised guidance and rule changes for expanded access for trial inelligible patients that will help make the procedures easier a little easier, and clarify when this use is appropriate.

I agree with you about trials being a mechanism for those will no means to get medical care. I was making a narrower point. I simply don’t think that allowing terminally-ill people to buy phase-I drugs will significantly change the incentives for phase-II testing for promising drugs.

Those who think it will are making the argument that the terminally ill who want and can afford to pay out of pocket for experimental drugs make up such a large market that a significant number of companies will stop testing at phase-I.

So, I could be wrong. It is possible that terminally-ill people buying phase-I drugs would significantly reduce the incentive for continuing testing. However, I have seen no evidence of that. I think the burden falls on those who would restrict freedom to justify that restriction, and something more quantitative than I have seen would be required.

It’s deja vu all over again. Our health care system has been through this battle before. In the 1990’s, health plans were sued to provide coverage of for autologous bone marrow transplants and high dose chemotherapy for cancer patients, despite the lack of evidence that the therapy worked. Once patients started winning lawsuits, it became very difficult to enroll patients in phase III trials. Once the trials were performed, lo and behold, no clinical benefit could be demonstrated. See http://content.healthaffairs.org/cgi/reprint/20/5/101.pdf

As Santayana said, “Those who cannot learn from history are doomed to repeat it.”